The primary objective of this study is to evaluate the effectiveness and feasibility of directly observed therapy (DOT) using patient-nominated peer supervisors as a strategy to improve adherence to highly active antiretroviral therapy (HAART) in HIV-infected adults in South Africa. This country has the worst and fastest growing HIV epidemic in the world. The benefit of HAART has been shown both at the individual and public health levels by reducing morbidity, mortality, vertical and possibly horizontal HIV transmission. However expenses, feasibility, long-term adherence and effective delivery of HAART remain formidable barriers, even in the healthier nations. Recently, international initiatives have provided hope for widespread use of HAART in sub-Saharan Africa at affordable cost. In addition, simplified (once daily) HAART combinations regimens with DOT may help to achieve high levels of treatment adherence, a key component for long-term viral suppression, and hence treatment success. Peer advocates have been used to improve adherence with medical therapies in a variety of settings. In order to investigate the potential utility of Peer-DOT-HAART regimens in South Africa, we propose to conduct a randomized trial in which 200 patients will be randomized to either Peer-DOT-HAART or self-administration of a once-daily combination of didanosine, lamivudine, and efavirenz for 24 months. The specific aims of this study are: 1) to evaluate the impact of Peer-DOT-HAART on control of viral burden and immune restoration as measured by CD4 lymphocytes count and HIV viral load; 2) to evaluate the impact of DOT-HAART on treatment adherence; 3) to determine the proportion of genotypic HAART resistance in the DOT vs. self-administered HAART arms; 4) to compare incidence of new or recurrent opportunistic infection in the DOT vs. self-administered HAART. We hypothesize that the patients on the once daily observed regimen will have high levels of treatment adherence and hence more effective in controlling viral burden, thereby limiting the likelihood of virologic failure, drug resistance, and disease progression. This study will generate critical data on an alternative community-based approach of delivering HAART which may become a standard of care applicable throughout sub-Saharan Africa and the whole developing world.